Human T follicular helper clones seed the germinal center-resident regulatory pool
Open accessPublished version of a preprint
Abstract
The mechanisms by which FOXP3 + T follicular regulatory (Tfr) cells simultaneously steer antibody formation toward microbe or vaccine recognition and away from self-reactivity remain incompletely understood. To explore underappreciated heterogeneity in human Tfr cell development, function, and localization, we used paired TCRVA / TCRVB sequencing to distinguish tonsillar Tfr cells that are clonally related to natural regulatory T cells (nTfr) from those likely induced from T follicular helper (Tfh) cells (iTfr). The proteins iTfr and nTfr cells differentially expressed were used to pinpoint their in situ locations via multiplex microscopy and establish their divergent functional roles. In silico analyses and in vitro tonsil organoid tracking models corroborated the existence of separate T reg -to-nTfr and Tfh-to-iTfr developmental trajectories. Our results identify human iTfr cells as a distinct CD38 + , germinal center–resident, Tfh-descended subset that gains suppressive function while retaining the capacity to help B cells, whereas CD38 − nTfr cells are elite suppressors primarily localized in follicular mantles. Interventions differentially targeting specific Tfr cell subsets may provide therapeutic opportunities to boost immunity or more precisely treat autoimmune diseases.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Recent data identify FOXP3+ acquisition by conventional naive T cell-derived Tfh cells in late murine as well as in human germinal centers.
“Of interest, recent data identify FOXP3 + acquisition by conventional naive T cell-derived Tfh cells in late murine 79 as well as in human germinal centers. 80”
From Autoantigen-specific CD4+ T cells acquire an exhausted phenotype and persist in human antigen-specific autoimmune diseases (2024) · cites this paper as [80]
These cells acquire suppressive function but maintained B helper cell function.
“These cells acquire suppressive function but maintained B helper cell function. 80”
From Autoantigen-specific CD4+ T cells acquire an exhausted phenotype and persist in human antigen-specific autoimmune diseases (2024) · cites this paper as [80]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Integrated analysis of multimodal single-cell data
Hao, Y., Hao, S., Andersen-Nissen, E., Mauck, W. M., Zheng, S., Butler, A., Lee, M. J., Wilk, A. J., Darby, C., Zagar, M., et al. (2020) · doi:10.1101/2020.10.12.335331 · Cited by 15,508 · see citing works
Trapnell, C., Cacchiarelli, D., Grimsby, J., Pokharel, P., Li, S., Morse, M., Lennon, N. J., Livak, K. J., Mikkelsen, T. S., & Rinn, J. L. (2014) · Nature Biotechnology · doi:10.1038/nbt.2859 · Cited by 7,314 · see citing works
Victora, G. D., & Nussenzweig, M. C. (2012) · Annual Review of Immunology · doi:10.1146/annurev-immunol-020711-075032 · Cited by 1,878 · see citing works
Deep profiling of mouse splenic architecture with CODEX multiplexed imaging
Goltsev, Y., Samusik, N., Kennedy-Darling, J., Bhate, S., Hale, M., Vazquez, G., Black, S., & Nolan, G. P. (2018) · Cell · doi:10.1016/j.cell.2018.07.010 · Cited by 1,501 · see citing works
Thornton, A. M., Korty, P. E., Tran, D. Q., Wohlfert, E. A., Murray, P. E., Belkaid, Y., & Shevach, E. M. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0904028 · Cited by 1,382 · see citing works
Foxp3+ follicular regulatory T cells control the germinal center response
Linterman, M. A., Pierson, W., Lee, S. K., Kallies, A., Kawamoto, S., Rayner, T. F., Srivastava, M., Divekar, D. P., Beaton, L., Hogan, J. J., et al. (2011) · Nature Medicine · doi:10.1038/nm.2425 · Cited by 1,292 · see citing works
A chemokine-driven positive feedback loop organizes lymphoid follicles
Ansel, K. M., Ngo, V. N., Hyman, P. L., Luther, S. A., Förster, R., Sedgwick, J. D., Browning, J. L., Lipp, M., & Cyster, J. G. (2000) · Nature · doi:10.1038/35018581 · Cited by 1,282 · see citing works
Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions
Chung, Y., Tanaka, S., Chu, F., Nurieva, R. I., Martinez, G. J., Rawal, S., Wang, Y.-H., Lim, H., Reynolds, J. M., Zhou, X.-H., et al. (2011) · Nature Medicine · doi:10.1038/nm.2426 · Cited by 1,120 · see citing works
Schürch, C. M., Bhate, S. S., Barlow, G. L., Phillips, D. J., Noti, L., Zlobec, I., Chu, P., Black, S., Demeter, J., McIlwain, D. R., et al. (2020) · Cell · doi:10.1016/j.cell.2020.07.005 · Cited by 1,058 · see citing works
Greenwald, N. F., Miller, G., Moen, E., Kong, A., Kagel, A., Dougherty, T., Fullaway, C. C., McIntosh, B. J., Leow, K. X., Schwartz, M. S., et al. (2022) · Nature Biotechnology · doi:10.1038/s41587-021-01094-0 · Cited by 953 · see citing works
A B-cell-homing chemokine made in lymphoid follicles activates Burkitt's lymphoma receptor-1
Gunn, M. D., Ngo, V. N., Ansel, K. M., Ekland, E. H., Cyster, J. G., & Williams, L. T. (1998) · Nature · doi:10.1038/35876 · Cited by 825 · see citing works
IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses
Linterman, M. A., Beaton, L., Yu, D., Ramiscal, R. R., Srivastava, M., Hogan, J. J., Verma, N. K., Smyth, M. J., Rigby, R. J., & Vinuesa, C. G. (2010) · The Journal of Experimental Medicine · doi:10.1084/jem.20091738 · Cited by 803 · see citing works
Zotos, D., Coquet, J. M., Zhang, Y., Light, A., D’Costa, K., Kallies, A., Corcoran, L. M., Godfrey, D. I., Toellner, K., Smyth, M. J., et al. (2010) · The Journal of Experimental Medicine · doi:10.1084/jem.20091777 · Cited by 780 · see citing works
Molecular Mechanisms of Treg-Mediated T Cell Suppression
Schmidt, A., Oberle, N., & Krammer, P. H. (2012) · Frontiers in Immunology · doi:10.3389/fimmu.2012.00051 · Cited by 760 · see citing works
Masuda, N., Ohnishi, T., Kawamoto, S., Monden, M., & Okubo, K. (1999) · Nucleic Acids Research · doi:10.1093/nar/27.22.4436 · Cited by 683 · see citing works
scRepertoire: An R-based toolkit for single-cell immune receptor analysis
Borcherding, N. C., Bormann, N. L., & Kraus, G. (2020) · F1000Research · doi:10.12688/f1000research.22139.1 · Cited by 612 · see citing works
Cutting Edge: Direct Suppression of B Cells by CD4+CD25+ Regulatory T Cells
Lim, H. W., Hillsamer, P., Banham, A. H., & Kim, C. H. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.175.7.4180 · Cited by 600 · see citing works
Regulation of the Germinal Center Reaction by Foxp3+ Follicular Regulatory T Cells
Wollenberg, I., Agua‐Doce, A., Hernández, A., Almeida, C. F., Oliveira, V. G., Faro, J., & Graça, L. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1101328 · Cited by 599 · see citing works
Regulation of the Germinal Center Response
Stebegg, M., Kumar, S. D., Silva-Cayetano, A., Fonseca, V. R., Linterman, M. A., & Graca, L. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02469 · Cited by 349 · see citing works
scRepertoire: An R-based toolkit for single-cell immune receptor analysis
Borcherding, N. C., Bormann, N. L., & Kraus, G. (2020) · F1000Research · doi:10.12688/f1000research.22139.2 · Cited by 348 · see citing works
Modeling human adaptive immune responses with tonsil organoids
Wagar, L. E., Salahudeen, A. A., Constantz, C. M., Wendel, B. S., Lyons, M. M., Mallajosyula, V. V. A., Jatt, L. P., Adamska, J. Z., Blum, L. K., Gupta, N., et al. (2021) · Nature Medicine · doi:10.1038/s41591-020-01145-0 · Cited by 334 · see citing works
Origin and T Cell Receptor Diversity of Foxp3+CD4+CD25+ T Cells
Pacholczyk, R., Ignatowicz, H., Kraj, P. J., & Ignatowicz, L. (2006) · Immunity · doi:10.1016/j.immuni.2006.05.016 · Cited by 317 · see citing works
Germinal center B cells govern their own fate via antibody feedback
Zhang, Y., Meyer‐Hermann, M., George, L. A., Figge, M. T., Khan, M., Goodall, M. D., Young, S. P., Reynolds, A. T., Francesco Falciani, B., Waisman, A., et al. (2013) · The Journal of Experimental Medicine · doi:10.1084/jem.20120150 · Cited by 289 · see citing works
Lim, H. W., Hillsamer, P., & Kim, C. H. (2004) · Journal of Clinical Investigation · doi:10.1172/jci22325 · Cited by 288 · see citing works
Lim, H. W., Hillsamer, P., & Kim, C. H. (2004) · Journal of Clinical Investigation · doi:10.1172/jci200422325 · Cited by 260 · see citing works
Botta, D., Fuller, M. J., Marquez‐Lago, T. T., Bachus, H., Bradley, J., Weinmann, A. S., Zajac, A. J., Randall, T. D., Lund, F. E., León, B., et al. (2017) · Nature Immunology · doi:10.1038/ni.3837 · Cited by 235 · see citing works
MCMICRO: a scalable, modular image-processing pipeline for multiplexed tissue imaging
Schapiro, D., Sokolov, A., Yapp, C., Chen, Y., Muhlich, J. L., Hess, J. M., Creason, A., Nirmal, A. J., Baker, G. J., Nariya, M. K., et al. (2021) · Nature Methods · doi:10.1038/s41592-021-01308-y · Cited by 229 · see citing works
Deficiency in T follicular regulatory cells promotes autoimmunity
Fu, W., Liu, X., Lin, X., Han, F., Sun, L., Li, S., Chen, H., Tang, H., Lu, L., Jin, W., et al. (2018) · The Journal of Experimental Medicine · doi:10.1084/jem.20170901 · Cited by 219 · see citing works
Wing, J. B., Kitagawa, Y., Locci, M., Hume, H., Tay, C., Morita, T., Kidani, Y., Matsuda, K., Inoue, T., Kurosaki, T., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1705551114 · Cited by 211 · see citing works
Aloulou, M., Carr, E. J., Gador, M., Bignon, A., Liblau, R., Fazilleau, N., & Linterman, M. A. (2016) · Nature Communications · doi:10.1038/ncomms10579 · Cited by 190 · see citing works
Follicular regulatory T cells produce neuritin to regulate B cells
González-Figueroa, P., Roco, J. A., Papa, I., Núñez-Villacís, L., Stanley, M., Linterman, M. A., Dent, A. L., Cañete, P. F., & Vinuesa, C. G. (2021) · Cell · doi:10.1016/j.cell.2021.02.027 · Cited by 168 · see citing works
T follicular helper and T follicular regulatory cells have different TCR specificity
Maceiras, A. R., Almeida, S. C. P., Mariotti‐Ferrandiz, E., Chaara, W., Jebbawi, F., Six, A., Hori, S., Klatzmann, D., Faro, J., & Graça, L. (2017) · Nature Communications · doi:10.1038/ncomms15067 · Cited by 154 · see citing works
Fonseca, V. R., Agua‐Doce, A., Maceiras, A. R., Pierson, W., Ribeiro, F., Romão, V. C., Pires, A. R., Silva, S. L., Fonseca, J. E., Sousa, A. E., et al. (2017) · Science Immunology · doi:10.1126/sciimmunol.aan1487 · Cited by 150 · see citing works
Ritvo, P.-G., Churlaud, G., Quiniou, V., Flórez, L. V., Brimaud, F., Fourcade, G., Mariotti‐Ferrandiz, E., & Klatzmann, D. (2017) · Science Immunology · doi:10.1126/sciimmunol.aan0368 · Cited by 150 · see citing works
Spatial distribution and function of T follicular regulatory cells in human lymph nodes
Sayın, I., Radtke, A. J., Vella, L. A., Jin, W., Wherry, E. J., Buggert, M., Betts, M. R., Herati, R. S., Germain, R. N., & Canaday, D. H. (2018) · The Journal of Experimental Medicine · doi:10.1084/jem.20171940 · Cited by 138 · see citing works
Self-citationExpression of Foxp3 by T follicular helper cells in end-stage germinal centers
Jacobsen, J. T., Hu, W., Castro, T. B. R., Solem, S., Galante, A., Lin, Z., Allon, S. J., Mesin, L., Bilate, A. M. B., Schiepers, A., et al. (2021) · Science · doi:10.1126/science.abe5146 · Cited by 136 · see citing works
Circulating Follicular Regulatory T Cells Are Defective in Multiple Sclerosis
Dhaeze, T., Peelen, E., Hombrouck, A., Peeters, L. M., Wijmeersch, B. V., Lemkens, N., Lemkens, P., Somers, V. A., Lucas, S., Broux, B., et al. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1500759 · Cited by 131 · see citing works
Sandoval‐Montes, C., & Santos‐Argumedo, L. (2004) · Journal of Leukocyte Biology · doi:10.1189/jlb.0404262 · Cited by 126 · see citing works
Wen, Y., Yang, B., Lu, J., Zhang, J., Yang, H., & Li, J. (2016) · Neuroscience Letters · doi:10.1016/j.neulet.2016.07.049 · Cited by 90 · see citing works
Regulatory roles of IL-10–producing human follicular T cells
Cañete, P. F., Sweet, R. A., González-Figueroa, P., Papa, I., Ohkura, N., Bolton, H. A., Roco, J. A., Cuenca, M., Bassett, K., Sayın, I., et al. (2019) · The Journal of Experimental Medicine · doi:10.1084/jem.20190493 · Cited by 86 · see citing works
Romberg, N. D., Coz, C. L., Glauzy, S., Schickel, J., Trofa, M., Nolan, B. E., Paessler, M. E., Xu, M. L., Lambert, M. P., Lakhani, S. A., et al. (2018) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2018.06.012 · Cited by 78 · see citing works
Self-citationCD4+ follicular regulatory T cells optimize the influenza virus–specific B cell response
Lu, Y., Jiang, R., Freyn, A. W., Wang, J., Strohmeier, S., Lederer, K., Locci, M., Zhao, H., Angeletti, D., O’Connor, K. C., et al. (2020) · The Journal of Experimental Medicine · doi:10.1084/jem.20200547 · Cited by 54 · see citing works
Pahl, M. C., Coz, C. L., Su, C., Sharma, P. K., Thomas, R. M., Pippin, J. A., Cabrera, E. C., Johnson, M. E., Leonard, M. E., Lu, S., et al. (2022) · Genome biology · doi:10.1186/s13059-022-02691-1 · Cited by 45 · see citing works
Self-citationAdenosine deaminase-1 delineates human follicular helper T cell function and is altered with HIV
Tardif, V., Muir, R., Cubas, R. A., Chakhtoura, M., Wilkinson, P. A., Metcalf, T. U., Herro, R., & Haddad, E. K. (2019) · Nature Communications · doi:10.1038/s41467-019-08801-1 · Cited by 34 · see citing works
Coz, C. L., Bengsch, B., Khanna, C., Trofa, M., Ohtani, T., Nolan, B. E., Henrickson, S. E., Lambert, M. P., Olmsted, T., Despotovic, J. M., et al. (2019) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2019.08.007 · Cited by 32 · see citing works
Self-citationHuman CD38 regulates B cell antigen receptor dynamic organization in normal and malignant B cells
Camponeschi, A., Kläsener, K., Sundell, T., Lundqvist, C., Manna, P. T., Ayoubzadeh, N., Sundqvist, M., Thorarinsdottir, K., Gatto, M., Visentini, M., et al. (2022) · The Journal of Experimental Medicine · doi:10.1084/jem.20220201 · Cited by 31 · see citing works
Moysi, E., Estrada, P. M. D. R., Torres-Ruiz, F., Reyes‐Terán, G., Koup, R. A., & Petrovas, C. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.683396 · Cited by 29 · see citing works
(2021) · Methods in molecular biology · doi:10.1007/978-1-0716-1736-6 · Cited by 4 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Saggau, C., Bacher, P., Esser, D., Rasa, M., Meise, S., Mohr, N., Kohlstedt, N., Hutloff, A., Schacht, S.-S., Dargvainiene, J., et al. (2024) · Immunity · doi:10.1016/j.immuni.2024.08.005 · Cited by 79 · see citing works
Single-cell transcriptome landscape of circulating CD4+ T cell populations in autoimmune diseases
Yasumizu, Y., Takeuchi, D., Morimoto, R., Takeshima, Y., Okuno, T., Kinoshita, M., Morita, T., Kato, Y., Wang, M., Motooka, D., et al. (2024) · Cell Genomics · doi:10.1016/j.xgen.2023.100473 · Cited by 60 · see citing works
- Authors
- Le Coz, C., Oldridge, D. A., Herati, R. S., De Luna, N., Garifallou, J., Cruz Cabrera, E., Belman, J. P., Pueschl, D., Silva, L. V., Knox, A. V. C., Reid, W., Yoon, S., Zur, K. B., Handler, S. D., Hakonarson, H., Wherry, E. J., Gonzalez, M., & Romberg, N.
- Affiliations
- Division of Allergy and Immunology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA.
- Children's Hospital of Philadelphia (US)
- New York University (US)
- University of Pennsylvania (US)
- Corresponding author
- Romberg, Neil
- ORCID
- Venue
- Science Immunology
- Published
- 2023-04-14
- Volume
- 8
- Issue
- 82
- Pages
- eade8162-eade8162
- ISSN
- 2470-9468 (ISSN-L)
- PMC
- PMC10329285
- OpenAlex
- W4362705778
- Cited by
- 77
- References
- 48
- Citations by year
- 2026: 24 · 2025: 24 · 2024: 19 · 2023: 10
- FWCI
- 8.40
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Science Immunology (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Children's Hospital of Philadelphia
- Parker Institute for Cancer Immunotherapy
- Gray Foundation
- National Institutes of Health (CA210944, AI082630, AI117950, AI108545)
- National Heart, Lung, and Blood Institute (T32HL007775, R38HL143613)
- National Cancer Institute (T32CA009140, CA009140, P01CA210944)
- National Institute of Allergy and Infectious Diseases (R01AI115712, AI 082630, AI108545, R01AI146026, K08AI114852, AI 117950, AI115712, U19AI117950, R01AI155577, AI146026, U19AI082630, P01AI108545)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Life Sciences › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
- Keywords
- follicular regulatory T cells, T follicular helper cells, Foxp3, germinal center, tonsil, T cell receptor repertoire, natural regulatory T cells, induced regulatory T cells, CD38, B cell help, Treg differentiation, autoimmune disease therapy
- MeSH terms
- B-Lymphocytes, Clone Cells, T-Lymphocytes, Helper-Inducer, Humans, Germinal Center, T-Lymphocytes, Regulatory
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
